Strong Genetic Evidence of DCDC2 as a Susceptibility Gene for Dyslexia

Abstract

We searched for linkage disequilibrium (LD) in 137 triads with dyslexia, using markers that span the most-replicated dyslexia susceptibility region on 6p21-p22, and found association between the disease and markers within the VMP/DCDC2/KAAG1 locus. Detailed refinement of the LD region, involving sequencing and genotyping of additional markers, showed significant association within DCDC2 in single-marker and haplotype analyses. The association appeared to be strongest in severely affected patients. In a second step, the study was extended to include an independent sample of 239 triads with dyslexia, in which the association--in particular, with the severe phenotype of dyslexia--was confirmed. Our expression data showed that DCDC2, which contains a doublecortin homology domain that is possibly involved in cortical neuron migration, is expressed in the fetal and adult CNS, which--together with the hypothesized protein function--is in accordance with findings in dyslexic patients with abnormal neuronal migration and maturation.

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

“…Multivariate linkage analysis had previously shown that the DYX2 QTL influenced variability shared by all the DD measures but did not influence IQ, 24 and univariate quantitative linkage analysis using IQ-adjusted traits refined the linkage signal. 17 Therefore, all quantitative measures used in the present study were IQ-adjusted as in Francks et al 17 As previous evidence had indicated that the DYX2 locus influences the most severely affected with reading disability, 17,21,25 we used the same subsample of sibships as in Francks et al, 17 that is scoring below a mean measure calculated on phonological decoding ability and orthographic coding, which were the two measures contributing most to the linkage signal. This selection yielded 126 families, including 313 siblings.…”

“…To attempt replication of the association observed in DCDC2, we selected those polymorphisms from the German and US studies 20,21 that showed the most significant association either as single markers, or as part of a haplotype. Markers genotyped in both the Oxford and Cardiff samples were the two SNPs (rs807724 and rs1087266) and the intronic deletion identified by Meng et al, 20 and the two SNPs forming the haplotype implicated by Schumacher et al 21 (rs793862 and rs807701).…”

“…Markers genotyped in both the Oxford and Cardiff samples were the two SNPs (rs807724 and rs1087266) and the intronic deletion identified by Meng et al, 20 and the two SNPs forming the haplotype implicated by Schumacher et al 21 (rs793862 and rs807701). The compound STR described by Meng et al 20 was also genotyped in the Cardiff sample.…”

“…The deletion, in combination with 10 rare STR alleles, showed significant association with different reading traits. Using a categorical definition of dyslexia based on spelling impairment, Schumacher et al 21 also found association with variation within the DCDC2 gene in two independent trio samples of German descent, most significantly with a two-marker haplotype in intron 7 comprised of the SNPs rs793862 and rs807701. This association appeared strongest in the most severely affected patients of both samples.…”

“…We have analyzed a new selection of SNPs covering KIAA0319 and DCDC2, including the DCDC2 markers that showed significant association with DD in previous studies. 20,21 Materials and methods…”